Are we doing any better? HSP Postgraduate Course November 21, 2013 - - PowerPoint PPT Presentation

HEPATIC ENCEPHALOPATHY Are we doing any better?

HSP Postgraduate Course November 21, 2013 Radisson Blu Hotel Cebu City Evelyn B. Dy, M.D.

Practice Guidelines ACG 2001

HEPATIC ENCEPHALOPATHY

DEFINITION PATHOGENESIS CLINICAL FEATURES TREATMENT

HEPATIC ENCEPHALOPATHY

Spectrum of neuropsychiatric abnormalities: impairment of sleep-wake cycle, cognition, memory, consciousness, motor-sensory function. Patients with liver dysfunction. After exclusion of metabolic, infectious, intravascular or space-occupying lesion.

SUBTYPES OF HEPATIC ENCEPHALOPATHY

PATHOGENESIS

Ammonia Hypothesis GABA Hypothesis Neurotoxins Acetylcholinesterase Hyponatremia Astrocyte swelling and dysfunction

AMMONIA HYPOTHESIS

NH3

• Produced by degradation of AA amines in the GIT
• Enterocyte convert gluatamine to glutamate and NH3 by

glutaminase NH3 detoxified by the liver by conversion to urea Kreb's cycle

Cirrhosis: NH3 is due to functioning of hepatocytes Portosystemic shunting divert NH3 to the systemic circulation Skeletal muscle contains glutamine synthetase which helps consume NH3 by converting glutamate to glutamine Temporary means of detoxifying NH3 The kidneys can both produce ammonia thru glutamine and excrete ammonia as NH4 thru glutamine synthetase.

• In Acidosis: NH4 is released in the urine.
• In Alkalosis: decreased loss of NH4 in the urine.

GABA HYPOTHESIS

Gamma Butyric Acid (GABA)

• Neuroinhibitory substance produced in the GIT
• GABA receptor complex contains binding sites for

GABA, Benzodiazepines.

• permit influx of chloride ions into the postsynaptic

neuron generating inhibitory postsynaptic potential

NEUROTOXINS ACCUMULATION HYPOTHESIS

Ammonia, Manganese, False transmitters, Short chain fatty acids production of peripheral type benzodiazepine receptor (PTBR) or 18-kda translocator protein (TSPO) Stimulates conversion of cholesterol to pregnenolone to neurosteroids Binds to gamma receptor complex increasing inhibitory neurotransmissions

ACETYLCHOLINESTERAS E HYPOTHESIS

Acetylcholinesterase results to Acetylcholine which is a neurotransmitter at the neuromuscular junction

ASTROCYTE SWELLING and DYSFUNCTION

Astrocyte

• Key role in the regulation of blood brain barrier
• Maintain electrolyte homeostasis
• Provide nutrients and neurotransmitter precursors to

neurons

ALZHEIMER TYPE 2 ASTROCYTOSIS

Large pale nucleus, prominent nucleolus Leads to neuronal edema Neuronal dysfunction

HYPONATREMIA - "Second Hit"

Causes depletion of astrocyte osmolytes

• Cells cannot compensate well during period of

hyperammonemia or inflammation Astrocyte swelling, cerebral edema, oxidative and nitrosative and astrocyte dysfunction.

PATHOPHYSIOLOGY of HEPATIC ENCEPHALOPATHY

CLINICAL FEATURES: West- Haven Criteria

CLINICAL FEATURES

Stage 0-1 Covert hepatic encephalopathy (Minimal hepatic encephalopathy) Stage 2-4 Overt hepatic encephalopathy

COVERT HEPATIC ENCEPHALOPATHY

Low level cognitive dysfunction in 70% of patients with cirrhosis Decrease attention and executive dysfunction Depressed psychomotor speed and visuomotor activity Delayed choice reactive time Impaired fitness to drive

DIAGNOSIS OF COVERT HEPATIC ENCEPHALOPATHY

NEW TESTS FOR DIAGNOSIS OF CHE

A.Inhibitory Control Test (ICT)

• Sensitivity 87%, specificity 77%
• http//www.hecme.tv. (HEcme TV Website)

B.CNS Vital Signs (CNSVS)

• Sensitivity 85%, specificity 64%
• http://www.cnsvs.com (CNSVS Website)
• Presented at DDW 2012

TREATMENT STRATEGIES for HEPATIC ENCEPHALOPATHY

• 1. Management of precipitating factors.
• 2. Reduction of NH3 and other toxins.
• 3. Modulation of fecal flora.
• 4. Modulation of neurotransmission.
• 5. Correction of nutritional deficiencies.
• 6. Reduction of inflammation.
• 7. Molecular adsorbent recirculating system (MARS Gambro) - liver dialysis

PRECIPITATING FACTORS

MANAGEMENT OF PRECIPITATING FACTORS

Hepatic encephalopathy is usually precipitated by an event. Careful history and physical examination are required to identify less dramatic and contributing cause.

REDUCTION of NH3 and OTHER TOXINS

• 1. Non-absorbable dissacharide (Lactulose)

Mechanism of action

• Cathartic
• Acidification of gut lumen favors conversion of NH3

to nH4 ion

• Reduction of urease producing bacteria (Prebiotic)

Cirrhosis

• 30-45% Overt HE (Annual risk 20%)
• 60-80% Covert HE

EFFECTS of LACTULOSE vs NO TREATMENT in CIRRHOTICS WITHOUT ANY EPISODE OF OVERT HE

66% of the covert hepatic encephalopathy in the Lactulose group showed improvement. Followed monthly for 12 months

Agrawal et al. Primary prophylaxis of encephalopathy in patients with cirrhosis: An open-labeled randomized controlled trial of lactulose vs no lactulose. J. Hepatol 2012.

Number of Patients Overt HE Percentage

55 with Lactulose 6 11 50 w/o Lactulose 15 30

SECONDARY PROPHYLACTIC THERAPY FOR PREVENTION OF OHE IN CIRRHOTIC PATIENTS WHO HAVE EXPERIENCED AN OHE EPISODE

REDUCTION of NH3 and OTHER TOXINS

• 2. NH3 Scavengers
• a. L-ornithine L-aspartate (LOLA)
• substrate for glutamate transaminase which results in

increase glutamate levels. Glutamate with NH3 produce glutamine in the presence of glutamine synthetase.

• b. L-ornithine, Phenylacetate (LOPA)
• increase supply of ornithine to the urea cycle

• c. Sodium benzoate, Sodium phenylbutyrate, Sodium phenylacetate,

Glycerol phenylbutyrate

• Sodium benzoate interacts with glycine to form hippurate

excretion of hippurate leading to NH3 loss.

• limited by risk of sodium overload
• Sodium phenylbutyrate is converted to phenylacetate reacts

with glutamine to form phenylacetylglutamine excreted in urine with loss of NH3 ions

• Sodium phenylbutyrate (Buphenyl)
• IV Sodium phenylacetate (Ammonul)
• Glycerol phenylbutyrate (Ravicti)
• FDA approved for treatment of hyperammonemia

associated with urea cycle disorders

• d. Zinc
• Increase activity of ornithine transcarbamylase, an

enzyme in urea cycle

• Zinc sulfate or Zinc acetate 600 mg/day

• e. L-carnitine
• Improved HE symptoms in several studies
• Decrease brain NH3 uptake

• f. AST-120 (OCERA)
• Spherical carbon adsorbent
• Adsorbs small molecules not only NH3, but also

Liposaccharides, and Cytokines.

• Pilot study: Efficacy equivalent with Lactulose
• Large study recently completed.

MODULATION of FECAL FLORA

• 1. ANTIBIOTICS
• decrease concentration of ammoniagenic bacteria
• A. Neomycin, Metronidazole, Paromomycin, Vancomycin
• limitation in safety and resistance (ototoxicity, nephrotoxicity, neurotoxicity)
• B. Rifaximin
• poorly absorbed relative of Rifamycin
• broad antibacterial activity for aerobes and anaerobes
• approved by US FDA for hepatic encephalopathy

SECONDARY PROPHYLACTIC THERAPY FOR PATIENT IN REMISSION FOR OVERT HEPATIC ENCEPHALOPATHY

Randomized double blind study: Rifaximin 555 mg BID vs Placebo

Number of Patients Number of Patients Who Developed HE Percentage

• f Patients

Who Developed HE Rifaximi n

140 31 22.1%

Placebo

159 73 45.9%

• 2. Prebiotics (Lactulose, Fermentable fibers)

Probiotics (Bifidobacteria, Lactobacilli)

• Reduce urease-producing species
• Improved overall liver function
• Reduced translocation of bacteria (Endotoxemia) by

ameliorating hyperdynamic circulation

• 3. Acarbose (Alpha-Glucosidase Inhibitor)
• Reduce glucose absorption, promotes primarily

saccharolytic bacteria reducing NH3 generation.

• Double-blind randomized trial among DM patients with

mild HE showed improvement in number connection test and HE grading.

MODULATIONS of NEUROTRANSMISSION

Drugs Used to Target Altered Neurotransmission

Flumazenil Used when benzodiazepine is trigger factor Naloxone Bromocriptine Levodopa Rivastigmine Acetylcholinesterase inhibitor pilot study showed some benefit

CORRECTION of NUTRITIONAL DEFICIENCIES

Factors Involved in Poor Nutrition

• Poor Dietary Absorption (Fat soluble vitamins)
• Poor Intake (Weakness, ascites)
• Baseline Hypercatabolic State
• Zinc Deficiency
• Skeletal Muscle Depletion

CORRECTION of NUTRITIONAL DEFICIENCIES

Daily Protein Intake: 1.0-1.5 g/kg/day depending on the degree of hepatic decompensation

• ESPEN Guidelines 1997

Branched-chain Amino Acids

• Prevents synthesis of false neurotransmitters
• Corrects Fischer's ratio balance between AAA and BCAA
• Reduces catabolism and muscle breakdown

Zinc Supplementation

• Zinc - cofactor in the urea cycle

L-ornithine L-aspartate/L-ornithine phenylacetate L-carnitine or its acetylated form

REDUCTION of INFLAMMATION

Cirrhotics are in a proinflammatory state

• Increase levels of endotoxin, tumor necrosis factor,

cytokines Antibiotics improved hyperdynamic circulation of cirrhosis; reduced the risk of hepatorenal syndrome

POTENTIAL DRUGS with ANTI-INFLAMMATORY ROLE

Pentoxyfylline: anti-TNF alpha activity reduce complication of cirrhosis and hepatic encephalopathy AST-120: bind small molecule in the gut, TNF lipopolysaccharide and endotoxin

REVERSIBILITY of HEPATIC ENCEPHALOPATHY

" Those who recovered from an episode of overt hepatic encephalopathy appeared to improve with drug therapy with no residual neurocognitive impairment"

• This statement has been challenged.

Sotil et al. 2009 39 Patients with Liver transplantation 25 Patients who have HE before liver transplant performed worse on psychomotor test 14 Patients with no history of HE

Garcia-Martinez et al. 2011

• 52 Patients with liver transplant
• Patients with history of HE prior to liver transplant

performed worse in the global cognition function test; brain volume (MRI) was smaller.

• Episodes of hepatic encephalopathy may lead to neurologic

injury that is not reversible.

• Aggressive prophylactic therapy to prevent overt hepatic

encephalopathy in patients awaiting transplants.

SUMMARY

Hepatic Encephalopathy (HE) is a spectrum of neuropsychological dysfunction in patients with liver dysfunction after exclusion of other metabolic, infectious and brain disease. Pathophysiology involves overproduction, reduced metabolism of various neurotoxins particularly ammonia. Recent hypothesis implicates astrocytes dysfunction, low- grade cerebral edema as a final common pathway.

SUMMARY

Management is multifaceted.

• Careful identification and amelioration of precipitating

factors.

• Lactulose remain the mainstay in therapy. Prophylactic

use of lactulose in patients with or without previous episodes of overt hepatic encephalopathy showed encouraging results and may impact success in liver transplant candidates.

SUMMARY

• Rifaximin - a non-absorbable antibiotic replaces the more toxic antibiotics

like Neomycin.

• Prebiotics/Probiotics, other potential treatment options like:
• L-ornithine L-aspartate (LOLA)
• L-ornithine phenylacetate (LOPA)
• L-carnitine
• Acarbose
• AST-120
• Rivastigmine

Needs further validation in larger trial.

SUMMARY

• Newer diagnostic tools suitable in community practice to

diagnose covert hepatic encephalopathy is now available

• nline.
• Inhibitory Control Test (ICT)
• CNS Vital Signs (CNSVS)

Hepatic Encephalopathy - Are We Getting Better?

• Yes.

THANK YOU